The present invention relates to a process for the production of a cyclo acid, namely of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, which is an important intermediate in the multi-stage process for the manufacture of biotin (vitamin H).
The production of the aforementioned cyclo acid starting from meso-2,3-bis(benzylamino)-succinic acid in the form of its dialkali metal salt is known. Thus, for example, Seiter, U.S. Pat. No. 5,151,525 describes such a process in which phosgene is used as the reagent in an alkaline aqueous/organic two-phase solvent system for the linkage of the two secondary nitrogen atoms via a carbonyl group with resulting ring formation. In this case, anisole is employed as the essentially water-immiscible solvent for the reaction.
However, as is known, the reagent phosgene is highly toxic and, moreover, potentially explosive under the influence of other gases or certain reaction liquids, so that its use is extremely dangerous when it is carelessly handled or supervised, and special precautions are required in its transport, storage and use, e.g. the employment of safety devices in the apparatus.
An object of the present invention is to provide a process that overcomes certain of the above-referenced disadvantages for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid in the form of its dialkali metal salt using an alternative reagent for the ring formation. This object is achieved surprisingly well with the alternative reagent carbonic acid bis(trichloromethyl ester), also known as xe2x80x9cbis(trichloromethyl) carbonatexe2x80x9d orxe2x80x94abbreviated and referred to repeatedly hereinafterxe2x80x94xe2x80x9ctriphosgene,xe2x80x9d and in other respects by carrying out the process under particular reaction conditions.
One embodiment of the present invention is a process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid starting from meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt, which process includes reacting meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with triphosgene in a two-phase solvent system consisting of an aqueous alkali hydroxide solution and an organic solvent at a temperature not exceeding about 50xc2x0 C., and converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt, which is present in the aqueous phase, into the desired 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid by acidification.
Another embodiment of the invention is a process for preparing 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid. This process includes reacting an aqueous solution of meso-2,3-bis(benzylamino)-succinic acid with an alkali metal hydroxide solution to form an alkaline aqueous solution of meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt. Meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt is then reacted at a temperature below about 50xc2x0 C. with triphosgene in a two-phase solvent system, the two-phase solvent system consisting of an aqueous phase of an aqueous alkali hydroxide solution and an organic phase of an organic solvent. The resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidine-dicarboxylic acid dialkali metal salt in the aqueous phase is then acidified to form 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid.
The following Reaction Scheme is a structural representation of the process in accordance with the invention: 
In the above Reaction Scheme, the alkali metal ion M+ is either the sodium ion or the potassium ion, preferably the potassium ion, so that the disodium or dipotassium salt, preferably the latter, is used as the starting material for the process in accordance with the invention.
The triphosgene used in the present process is a white, crystalline product in the pure state with a melting point of 78xc2x0 C.-80xc2x0 C. It may be distilled without decomposition at a boiling point of 203xc2x0 C. to 206xc2x0 C. under atmospheric pressure (760 mm Hg/0.1013 MPa). Its decomposition temperature is above 350xc2x0 C. Triphosgene decomposes only slowly in air and may therefore be significantly safer to handle than phosgene in air. As is known, triphosgene may be produced in good yield and quality by the photochlorination of dimethyl carbonate and has also been commercially available in large amounts for many years.
For the production of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt, the acid itself is suspended in water, preferably deionized water, and the resulting suspension is treated with an alkali metal hydroxide solution, i.e. sodium or potassium hydroxide solution, preferably potassium hydroxide solution, generally at a pH value of about 9 to about 14, preferably at a pH value of about 12 to about 13. Such a treatment yields a clear, alkaline aqueous solution of the desired dialkali metal salt. Suitable amounts of water and added alkali metal hydroxide solution are used to ensure that the concentration of the meso-2,3-bis-(benzylamino)-succinic acid dialkali metal salt formed amounts to about 5 to about 20 weight percent, preferably about 10 to about 15 weight percent, based on the total weight of the resulting clear alkaline aqueous solution at a pH of about 9 to about 14. The concentration of the added alkali metal hydroxide solution is not critical, although it amounts to about 45-50 weight percent when commercial alkali metal hydroxide solution, e.g. potassium hydroxide solution, is used.
In the present invention, the two-phase solvent system consisting of aqueous alkali metal hydroxide solution and an organic solvent, in which the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt and the triphosgene are reacted with one another, is formed by combining the above-described clear alkaline aqueous solution of the first reaction participant with a solution of the triphosgene in the organic solvent. An aprotic organic solvent may be used as the organic solvent. Representative, non-limiting examples of aprotic organic solvents that may be used in the present invention include an aliphatic or cyclic ether, e.g. diethyl ether or, respectively, tetrahydrofuran or dioxan; an aliphatic or alicyclic hydrocarbon, e.g. hexane, octane or cyclohexane; an aliphatic or cyclic ester, e.g. ethyl acetate or xcex3-butyrolactone; or an aromatic hydrocarbon, e.g. benzene or toluene. Tetrahydrofuran or toluene is preferably used as the organic solvent. The concentration of the solution of the triphosgene in the solvent may vary, its upper limit depending, of course, on the employed solvent. The concentration of the triphosgene is, however, not critical, although on ecological and economical grounds it is preferably as high as possible.
In the combination of the alkaline aqueous solution of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt with the solution of the triphosgene in the organic solvent (the xe2x80x9creaction participantsxe2x80x9d), the former solution is heated to an elevated temperature in the range of about 30xc2x0 C. to about 50xc2x0 C., preferably in the temperature range of about 40xc2x0 C. to about 45xc2x0 C. prior to the combination. If desired, the solution of the triphosgene may also be heated to the corresponding temperature prior to the combination. The heating may also be effected for the first time during the course of the combination or thereafter.
The sequence of combining the reaction participants is not critical, i.e. the solution of the triphosgene may be added to the alkaline aqueous solution of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt or the alkaline aqueous solution may be added to the solution of the triphosgene. The former sequence is preferably effected. In this case, it has been found to be advantageous to add the solution of the triphosgene rather slowly and continuously, e.g. dropwise. In order to achieve a good intermixing during the combination, the mixture is suitably stirred or otherwise intermixed.
With respect to the relative amounts of meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt and triphosgene after completion of the combination, the molar ratio of triphosgene:meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt is about 0.33:1 to about 10:1, preferably about 1.5:1 to about 5:1. The range of about 2:1 to about 4:1 is especially preferred.
During the reaction of the triphosgene with the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt in the two-phase solvent system, the pH value of the aqueous phase is held in the range of about 8.5 to about 13, preferably in the range of about 9.5 to about 10.5. In order to maintain this pH range, aqueous sodium or potassium hydroxide solution is added as required simultaneously with the combination of the reaction participants or after completion of the combination. The concentration of the sodium or potassium hydroxide solution is not critical, although it amounts to about 5 to about 50 weight percent. It is especially preferred to use the same sodium or potassium hydroxide solution as that used for the production of the meso-2,3-bis(benzylamino)-succinic acid dialkali metal salt.
The reaction is effected at a temperature that does not exceed about 50xc2x0 C., generally at temperatures in the range of about 30xc2x0 C. to about 50xc2x0 C., preferably at temperatures of about 40xc2x0 C. to about 45xc2x0 C. The pressure is not critical; the reaction is normally carried out under atmospheric or slightly elevated pressure.
If desired, the process in accordance with the invention may be effected under an inert gas atmosphere. When an inert gas atmosphere is used, nitrogen or argon is especially suitable as the inert gas, nitrogen being preferred on an industrial scale.
After the addition (i.e., combination of the reaction participants) has been effected, which usually takes about 2 to 4 hours, the reaction is normally complete. The resulting two-phase mixture may then be worked up. The desired product, 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid in the form of its dialkali metal salt, is present mainly in the aqueous phase and is precipitated in the form of the free acid by acidification of this phase. Optionally, the previously separated aqueous phase or the entire two-phase mixture may be acidified. In the latter case, the resulting dicarboxylic acid migrates into the organic phase and must be isolated therefrom. The acid used in the acidification is mineral acid, preferably hydrochloric acid, hydrobromic acid, or sulfuric acid, of which hydrochloric acid is the most preferred mineral acid. The respective concentration and amount of the acid is selected so that the aqueous phase from which the product precipitates has a final pH value of about 0.5 to about 1.0. This ensures a good precipitation of the product. The sequence of the addition of the acid is also optional.
Where the aqueous phase has previously been separated from the organic phase, isolation of the product may be effected in any conventional manner, such as for example, by separation of the lower (heavier) aqueous phase in a separating funnel, decantation or centrifugation. Alternatively, the product is isolated from the organic phase after separation of the acidified aqueous phase, which may also be carried out by any conventional method. For example, the product may be isolated from the organic solvent by distillation.
The thus-isolated 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid may be washed with e.g., water, dried and, if desired, purified further.